Abstract

Cynomolgus macaques and rhesus macaques are nonhuman primate species widely used in drug metabolism studies. Cynomolgus CYP2D17, highly homologous to human CYP2D6, metabolizes human CYP2D6 substrates such as bufuralol and dextromethorphan, and the gene is expressed predominantly in liver. Although human CYP2D6 variants account for the variability of the enzyme properties among individuals and populations, genetic variants have not been investigated in CYP2D17. In the present study, CYP2D17 from 87 cynomolgus and 40 rhesus macaques was resequenced. The analysis found a total of 36 nonsynonymous variants, among which 5 were located in substrate recognition sites, the region important for protein function. Twenty-two variants were unique to cynomolgus macaques, of which 11 and 9 were found only in Indochinese and Indonesian cynomolgus macaques, respectively. Eight variants were unique to rhesus macaques. The functional characterization showed that two variant proteins (S188Y and V227I) heterologously expressed in Escherichia coli did not show substantial differences in the rate of bufuralol 1′-hydroxylation as compared with wild-type. However, measuring catalytic activities of the genotyped liver microsomes revealed that I297M and N337D were together significantly associated with higher rates, approximately 2.3- and 11.5-fold, of bufuralol 1′-hydroxylation and dextromethorphan O-demethylation, respectively, in the homozygotes than wild-type animals. The present study provided the first evidence that variability of a CYP2D-dependent metabolism in macaque liver is partly accounted for by CYP2D genotypes.